SYSTEM AND METHOD FOR CLEANING NOISY GENETIC DATA AND DETERMINING CHROMOSOME COPY NUMBER
Disclosed herein is a system and method for increasing the fidelity of measured genetic data, for making allele calls, and for determining the state of aneuploidy, in one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available. Poorly or incorrectly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related individuals. In accordance with one embodiment, incomplete genetic data from an embryonic cell are reconstructed at a plurality of loci using the more complete genetic data from a larger sample of diploid cells from one or both parents, with or without haploid genetic data from one or both parents. In another embodiment, the chromosome copy number can be determined from the measured genetic data, with or without genetic information from one or both parents.
1 . A method for measuring the amounts of target fetal chromosome segments in a maternal blood sample, comprising:
obtaining the maternal blood sample comprising fetal and maternal chromosome segments;
performing targeted PCR to amplify loci of interest on the fetal and maternal chromosome; and
measuring the amounts of amplified chromosome segments by performing next generation sequencing to determine the sequence of the amplified chromosome segments, thereby measuring the amounts of the target fetal chromosome segments in the maternal blood sample.
2 . The method of claim 1 , wherein the next generation sequencing is performed using sequencing by synthesis.
3 . The method of claim 1 , wherein the method further comprises performing a universal PCR to amplify chromosome segments comprising the loci of interest before the measuring step.
4 . The method of claim 1 , wherein the target fetal and maternal chromosome segments comprise one or more single nucleotide polymorphisms (SNPs).
5 . The method of claim 4 , wherein the detecting is performed irrespective of allele value.
6 . The method of claim 5 , wherein the target fetal chromosome segments map to chromosomes 13, 18, and/or 21.
7 . The method of claim 6 , wherein a ploidy is determined for chromosomes 13, 18, and/or 21 using the measured amounts of the target fetal chromosome segments.
8 . The method of claim 7 , wherein the method is used to detect trisomy at chromosomes 13, 18, and/or 21.
9 . The method of claim 7 , wherein the measuring comprises quantitative allele measurements.
10 . The method of claim 9 , wherein the detecting uses the quantitative allele measurements.
11 . The method of claim 10 , wherein determining the ploidy uses both allelic measurements and quantitative measurements of the measured amounts of amplified target fetal and maternal chromosome segments irrespective of allele value.
12 . The method of claim 9 , wherein the method further comprises comparing the measured amounts of amplified maternal chromosome segments with the measured amounts of amplified fetal chromosome segments.
13 . The method of claim 4 , further comprising measuring the amounts of chromosome segments on a reference chromosome in the maternal blood sample.
14 . The method of claim 13 , wherein the target fetal chromosome segments map to chromosomes 13, 18, and/or 21 and wherein the method is used to detect trisomy at chromosomes 13, 18, and/or 21.
15 . The method of claim 14 , wherein the detecting is performed irrespective of allele value.
16 . The method of claim 14 , wherein the measuring comprises quantitative allele measurements and wherein the detecting uses the quantitative allele measurements.
17 . The method of claim 3 , wherein the method further comprises performing a universal PCR to amplify chromosome segments comprising the loci of interest after the targeted PCR and before the measuring step.